Diabetes is a growing epidemic that currently affects over 25 million people in the US. The majority of these cases (90-95%) are type 2 diabetes, characterized by a diminished ability to respond to insulin. More alarming is that an estimated 54 million Americans have pre-diabetes, a condition that puts them at high risk for developing type 2 diabetes. New ways to manage this disease in an insulin independent manner are urgently needed. Recently, an unusual phospholipid, dilauroylphosphatidylcholine (PC 12:0-12:0; DLPC), has shown promising antidiabetic properties - lowering serum lipid levels, reducing fat accumulation in the liver, and improving glucose tolerance in diabetic mice when administered orally. Conditional knockout studies revealed that these effects were completely dependent on the orphan nuclear receptor liver receptor homologue-1 (LRH-1), thus identifying a new LRH-1 - DLPC signaling axis involved in bile acid metabolism and glucose homeostasis. We show that DLPC binds directly to LRH-1 and that DLPC binding completely blocks corepressor binding in vitro. To target this pathway for the treatment of diabetes it is critical t determine the fundamental mechanism governing the specific activation of LRH-1 by DLPC. We have determined the structure of the LRH-1 - DLPC complex to 1.9 , which shows that DLPC binds very differently than the current best LRH-1 synthetic agonists. We will capitalize on this structure along with several recent innovations in our lab to identify the mechanisms driving this unique activity to enhance the potency of potential therapeutics targeting LRH-1 for the treatment of metabolic diseases. The Specific Aims of this proposal are as follows: 1. To determine LRH-1's phospholipid specificity in vitro, 2. To define the interaction surface between DLPC and LRH-1 and to connect these interactions with receptor function, 3. To determine the structure and dynamics of the apoLRH-1 - corepressor complex PUBLIC HEALTH RELEVANCE: The diabetes epidemic, which currently impacts over 25 million people in the US, is rapidly growing. The majority of these cases (90-95%) are type 2 diabetics, characterized by a diminished ability to respond to insulin. Thus, new insulin-independent ways to manage this disease are urgently needed. Recently, an unusual phospholipid has shown promising antidiabetic properties acting through a protein termed LRH-1. We will target this LRH-1 - phospholipid signaling pathway to develop potential therapeutics for this widely prevalent disease.